A Phase 1 Randomized, Blinded Comparison of the Pharmacokinetics and Colonic Distribution of Three Candidate Rectal Microbicide Formulations of Tenofovir 1% Gel with Simulated Unprotected Sex (CHARM-02)

Abstract

CHARM-02 is a crossover, double-blind, randomized trial to compare the safety and pharmacokinetics of three rectally applied tenofovir 1% gel candidate rectal microbicides of varying osmolalities: vaginal formulation (VF) (3111 mOsmol/kg), the reduced glycerin vaginal formulation (RGVF) (836 mOsmol/kg), and an isoosmolal rectal-specific formulation (RF) (479 mOsmol/kg). Participants (n = 9) received a single, 4 ml, radiolabeled dose of each gel twice, once with and once without simulated unprotected receptive anal intercourse (RAI). The safety, plasma tenofovir pharmacokinetics, colonic small molecule permeability, and SPECT/CT imaging of lower gastrointestinal distribution of drug and virus surrogate were assessed. There were no Grade 3 or 4 adverse events reported for any of the products. Overall, there were more Grade 2 adverse events in the VF group compared to RF (p = 0.006) and RGVF (p = 0.048). In the absence of simulated unprotected RAI, VF had up to 3.8-fold greater systemic tenofovir exposure, 26- to 234-fold higher colonic permeability of the drug surrogate, and 1.5- to 2-fold greater proximal migration in the colonic lumen, when compared to RF and RGVF. Similar trends were observed with simulated unprotected RAI, but most did not reach statistical significance. SPECT analysis showed 86% (standard deviation 19%) of the drug surrogate colocalized with the virus surrogate in the colonic lumen. There were no significant differences between the RGVF and RF formulation, with the exception of a higher plasma tenofovir concentration of RGVF in the absence of simulated unprotected RAI. VF had the most adverse events, highest plasma tenofovir concentrations, greater mucosal permeability of the drug surrogate, and most proximal colonic luminal migration compared to RF and RGVF formulations. There were no major differences between RF and RGVF formulations. Simultaneous assessment of toxicity, systemic and luminal pharmacokinetics, and colocalization of drug and viral surrogates substantially informs rectal microbicide product development.

Use of a Prospective Sex Diary to Study Anal Lubricant and Enema Use Among High Risk Men Who Have Sex With Men—Implications for Human Immunodeficiency Virus Prevention

“…No prior study provided data on consistency of product use; however, prior studies reported that 77-92% of men were willing to use a topical microbicide [4-5]. Since rectal microbicides for HIV prevention are currently in development [15, 21-24], our data support the need for further research to understand the product preferences of MSM and how they are used.…”

“…silicone-based lubricants) [6-14]. Given these potential harms, further investigation is ongoing to determine which product type would serve as the best drug delivery system while having the least harmful effect on the rectal mucosa [23-24]. …”

HIV Antiretroviral Pre‐Exposure Prophylaxis: Development Challenges and Pipeline Promise

“…Our group built on his work and prior nuclear medicine methods in using single photon emission computed tomography/computed tomography (SPECT/CT) to describe the dis‐tribution of substances applied to the vagina or rectum, including cell‐free and cell‐associated HIV surrogates after simulated vaginal and anal sex to identify the luminal distribution of interest for microbicides . We also dosed radiolabeled candidate microbicides followed by a radiolabeled HIV surrogate to assure the coincident distribution of microbicide and HIV target within the distal colon, which demonstrated the suitability of enema formulations, and raised concerns about the feasibility of delivering adequate intraluminal microbicide gel when applied as an anal lubricant . Three‐dimensional tube‐fitting of SPECT data enabled quantitative descriptions of drug and HIV surrogate distribution, which proved useful when comparing among competing rectal microbicide candidates …”

“…[67][68][69][70] We also dosed radiolabeled candidate microbicides followed by a radiolabeled HIV surrogate to assure the coincident distribution of microbicide and HIV target within the distal colon, which demonstrated the suitability of enema formulations, and raised concerns about the feasibility of delivering adequate intraluminal microbicide gel when applied as an anal lubricant. 59,71,72 Three-dimensional tube-fitting of SPECT STATE of the ART data enabled quantitative descriptions of drug and HIV surrogate distribution, which proved useful when comparing among competing rectal microbicide candidates. 58,69,71,73 Nonclinical viral challenge models.…”

“…This vehicle was modified to accommodate addition of 1% TFV in a more nearly iso‐osmolar (479 mOsm/kg) rectal formulation, named RF. CHARM 01 and CHARM 02 directly compared the three TFV 1% formulations (VF, RGVF, and RF) applied rectally and found RF was superior to or equivalent to the other two formulations in all categories—PK, PD, acceptability, and safety . In these studies, RGVF achieved higher tissue TFV‐DP concentrations than RF, but performed slightly less well than RF in the ex vivo explant HIV challenge, raising concern that local toxicity with the hyperosmolar RGVF may have eroded its protective effect compared to the more nearly iso‐osmolar RF—possibly a bell‐shaped efficacy curve.…”